A case-control study of phosphodiesterase-5 inhibitor use and Alzheimer's disease and related dementias among male and female patients aged 65 years and older supporting the need for a phase III clinical trial.

BACKGROUND: Phosphodiesterase-5 inhibitors (PDE5i) have been evaluated as a novel treatment for Alzheimer's disease and related dementias (ADRD), but two recent cohort studies have offered opposing conclusions. METHODS: We performed an unmatched case-control study using electronic medical records from a large healthcare system to evaluate the association of PDE5i use and ADRD in patients ≥65 years old. RESULTS: Odds of PDE5i exposure were 64.2%, 55.7%, and 54.0% lower in patients with ADRD than controls among populations with erectile dysfunction, benign prostatic hyperplasia, and pulmonary hypertension, respectively. We observed odds ratios less than unity among males and females and with exposure to the PDE5i sildenafil (Viagra®) and tadalafil (Cialis®). We also evaluated the odds of exposure to two other common treatments for pulmonary hypertension: endothelin receptor antagonists (ERA) and calcium channel blockers (CCB). The odds of ERA exposure were 63.2% lower, but the odds of CCB exposure were 30.7% higher, in patients with ADRD than controls among the population with pulmonary hypertension. CONCLUSIONS: Our results reconcile the opposing conclusions from the previous observational studies and support further research into using PDE5i for prevention and treatment of ADRD.

Interleukin-1 receptor antagonist inhibits arthrofibrosis in a post-traumatic knee immobilization model.

BACKGROUND: Therapies for arthrofibrosis after knee surgery are needed to prevent loss of joint function. Interleukin-1 receptor antagonists (IL-1RA) have shown promise in treating established arthrofibrosis in pilot clinical studies. The objective of this study was to evaluate the ability of intra-articular injection of IL-1RA to prevent knee joint contracture in a post-traumatic knee immobilization model. METHODS: 20 male Sprague Dawley rats were block randomized into two groups: control and IL-1RA. Rats underwent intra-articular surgical trauma of the right knee with placement of an immobilization suture, securing the knees in 150° flexion. On post-operative days 1 and 8, each group received a 0.1 ml intra-articular injection of either saline (control) or anakinra (IL-1RA:single dosage; 2.63 mg/kg). Rats were euthanized fourteen days after surgery and the immobilization femorotibial angles were measured on the operative limbs with the suture and musculature intact. Subsequently, musculature was removed and femorotibial angles were measured in the operative and non-operative limbs with a defined extension moment applied with the posterior capsule intact or cut. A contracture angle was calculated as the angular difference between the operative and non-operative limb. RESULTS: The immobilization knee flexion angle did not differ (P = 0.761) between groups (control: 152 ± 9; IL-1RA: 150 ± 11). The joint contracture angles (smaller angle = improved outcome) were reduced by 12 degrees on average in the IL-1RA group compared to the control for both the capsule intact (P = 0.024) and cut (P = 0.019) states. CONCLUSIONS: Intra-articular IL-1RA injection was found to diminish knee extension deficits associated with arthrofibrosis in a post-traumatic joint immobilization model.

Metoprolol Impairs ß1-Adrenergic Receptor-Mediated Vasodilation in Rat Cerebral Arteries: Implications for ß-Blocker Therapy.

The practice of prescribing ß-blockers to lower blood pressure and mitigate perioperative cardiovascular events has been questioned because of reports of an increased risk of stroke. The benefit of ß-blocker therapy primarily relies on preventing activation of cardiac ß1-adrenergic receptors (ARs). However, we reported that ß1ARs also mediate vasodilator responses of rat cerebral arteries (CAs), implying that ß-blockers may impair cerebral blood flow under some conditions. Here, we defined the impact of metoprolol (MET), a widely prescribed ß1AR-selective antagonist, on adrenergic-elicited diameter responses of rat CAs ex vivo and in vivo. MET (1-10 µmol/l) prevented ß1AR-mediated increases in diameter elicited by dobutamine in cannulated rat CAs. The ß1AR-mediated dilation elicited by the endogenous adrenergic agonist norepinephrine (NE) was reversed to a sustained constriction by MET. Acute oral administration of MET (30 mg/kg) to rats in doses that attenuated resting heart rate and dobutamine-induced tachycardia also blunted ß1AR-mediated dilation of CAs. In the same animals, NE-induced dilation of CAs was reversed to sustained constriction. Administration of MET for 2 weeks in drinking water (2 mg/ml) or subcutaneously (15 mg/kg per day) also resulted in NE-induced constriction of CAs in vivo. Thus, doses of MET that protect the heart from adrenergic stimulation also prevent ß1AR-mediated dilation of CAs and favor anomalous adrenergic constriction. Our findings raise the possibility that the increased risk of ischemic stroke in patients on ß-blockers relates in part to adrenergic dysregulation of cerebrovascular tone. SIGNIFICANCE STATEMENT: ß-Blocker therapy using second-generation, cardioselective ß-blockers is associated with an increased risk of stroke, but the responsible mechanisms are unclear. Here, we report that either acute or chronic systemic administration of a cardioselective ß-blocker, metoprolol, mitigates adrenergic stimulation of the heart as an intended beneficial action. However, metoprolol concomitantly eliminates vasodilator responses to adrenergic stimuli of rat cerebral arteries in vivo as a potential cause of dysregulated cerebral blood flow predisposing to ischemic stroke.

Using a Facebook group to facilitate faculty-student interactions during preclinical medical education: a retrospective survey analysis.

BACKGROUND: Strong learner-teacher relationships are associated with more successful learning outcomes. With shortened modular curricula and increased availability of online resources, fostering faculty interaction with preclinical medical students has become more challenging. We sought to enhance learner-teacher relationships by engaging in discussion with preclinical medical students in their own online space. METHODS: We utilized a closed Facebook discussion group, where faculty and students voluntarily joined in informal discussions and shared announcements related to their courses. The closed discussion group allowed only participating students and faculty to see others' posts within the group. This provided a platform to freely interact within the confines of the group while maintaining privacy for the personal Facebook accounts of both faculty and students. We utilized the discussion group through three separate organ system-based modules for 14 weeks. Afterward, students were asked to complete an anonymous, voluntary online survey about their experience. RESULTS: 94.1% (160/170) of enrolled second-year medical students joined the voluntary FB discussion group. There were 214 posts, 628 comments, and 4166 reactions in this discussion group during the three modules. Of the students in the group, 74.4% (119/160) responded to the online survey. Overall, students strongly agreed that the Facebook discussion group fostered better rapport with faculty, helped content learning, and improved emotional well-being. Also, they felt more comfortable seeking academic help after using the discussion group. They reported a slight preference for Facebook over email as a medium for asking questions, but no preference for either as a medium for distributing announcements. Students overwhelmingly recommended that the discussion group should be continued in future years. CONCLUSION: The Facebook discussion group was a free, efficient, and effective method of cultivating the learner-teacher relationship with the preclinical medical students, resulting in reported enhancement of learning and morale.